Alzheimer’s disease (AD) is the leading cause of dementia with a growing prevalence worldwide.¹ However, diagnosing and treating AD remains challenging due to the complexity of its pathophysiology.^1,2 Recently, the National Institute on Aging and the Alzheimer’s Association (NIA-AA) updated the 2018 framework for diagnosing and evaluating AD, revising the criteria to incorporate recent advancements in biomarkers.³ These updated criteria build on the fundamental principle that AD is defined biologically by distinct neuropathologic changes, rather than solely by syndromic presentation, enabling diagnosis through biomarkers.³ These biomarker-focused criteria thus serve as a bridge between research and clinical practice, offering general principles to guide the diagnosis and staging of AD in line with current scientific understanding.³

Early diagnosis of AD is crucial for reducing the risk of developing dementia and slowing disease progression.¹ However, no single test for the diagnosis of AD exists, thus diagnosis in the clinic is typically based on patient history, clinical symptoms, various neuropsychiatric, physical, and functional assessments, as well as imaging and blood tests.¹  However, clinical symptoms may be caused by other disorders and the same AD biology may present differently.³ The use of biomarkers may provide a more accurate diagnosis at an earlier phase of the disease and help exclude other related pathologies.² Significant advances in AD diagnostics have been made in recent years, particularly in the development of blood-based markers which is relatively accessible compared to positron emission tomography (PET) and cerebrospinal fluid (CSF) assays.³ These revised criteria thus highlight the different uses of these imaging and fluid biomarkers in AD diagnosis and staging.³

Biomarkers may be categorized as imaging biomarkers that measure cumulative effects, capture topographic information, and may represent insoluble aggregates in the case of amyloid and tau PET, or fluid biomarkers reflect the net rates of production/clearance of analytes at a given point in time.³ More importantly, biomarkers are sorted into three broad categories: 1) core biomarkers of AD neuropathologic change (ADNPC), 2) non-specific biomarkers that are important in AD but are also involved in other brain diseases, and 3) biomarkers of common non-AD co-pathologies (Table 1).³

^{Table 1. Categorization of fluid and imaging biomarkers}

^{Aβ: Amyloid beta; AD: Alzheimer’s disease; αSyn-SAA: Alpha synuclein seed amplification assay; CSF: Cerebrospinal fluid; CT: Computed tomography; FDG: Fluorodeoxyglucose; GFAP: Glial fibrillary acidic protein; MRI: Magnetic resonance imaging; MTBR: Microtubule-binding region; NfL: Neurofilament light chain; PET: Positron emission tomography; WMH: White matter hyperintensity}

Additionally, core AD biomarkers are divided into Core 1 and Core 2 which are differentiated by the timing of abnormality onset and intended use.³ Core 1 biomarkers are detectable in the initial stage of AD in both symptomatic and asymptomatic individuals, and include amyloid PET, CSF p-tau181/amyloid beta (Aβ) 42 ratio, and plasma p-tau217.³ Abnormalities in Core 1 biomarkers are thus proposed to be sufficient to diagnose AD.³ On the other hand, Core 2 biomarkers include tau PET, certain soluble tau fragments associated with tau proteinopathy (eg. MTBR-tau243), pT205, and non-phosphorylated mid-region tau fragments.³ As these biomarkers become abnormal later in the disease and are more closely linked with the onset of symptoms, they may be combined with Core 1 to stage biological disease severity, rather than as standalone diagnostic tests for AD.³ An integrated biological and clinical staging scheme was also described which acknowledges that common co-pathologies, cognitive reserve, and resistance may modify relationships between clinical and biological AD stages.³

It is important to note that these biomarker criteria are meant to assist and not replace the clinical evaluation of individuals with cognitive impairment.³ The detection of early/mild AD neuropathologic changes is less sensitive with imaging and fluid biomarkers compared with neuropathologic examination.³ These AD biomarkers are also intended for the evaluation of symptomatic individuals and not cognitively unimpaired individuals.³ As many of these biomarkers are currently being used in clinical trials, they may soon be used to guide clinicians in making decisions about treatments for AD.³

In summary, these revised criteria for diagnosis and staging AD incorporate recent advances in biomarkers, providing clinicians with greater flexibility to use PET scans, CSF, or plasma assays.³ While these criteria currently serve as a bridge between research and clinical care, formal guidelines for clinical practice will be published subsequently.³